The present invention is in the field of peptide and protein chemistry as it applies to human medicine. In particular, the invention relates to the preparation of soluble stable peptide and protein formulations that include nicotinamide and hydrophobic preservatives.
Nicotinamide is not a widely-recognized excipient in pharmaceutical formulations. For example, it is not mentioned as an excipient in the Handbook of Pharmaceutical Excipients, 2nd ed., A. Wade and P. Weller, Eds. (1994). However, nicotinamide is known to increase the solubility of sparingly-soluble, non-protein, low molecular weight compounds, such as, certain piperazido and piperazino compounds [Fawzi, et al., J. Pharmaceut. Sci. 69:104-106 (1980)], anti-cancer nucleoside analogs [Truelove, et al., Int. J. Pharmaceutics 19:17-25 (1984)], paracetamol [Hamza, et al., Drug Dev. Industr. Pharmacy 11:1577-1596 (1985)], diazepam, griseofulvin, progesterone, 17xcex2-estradiol, and testosterone [Rasool, et al., J. Pharmaceut. Sci. 80:387-393 (1991)], the phenothiazine derivative, moricizine [Hussain, et al., J. Pharmaceut. Sci. 82:77-79 (1993)], and riboflavin [Coffman, et al., J. Pharmaceut. Sci. 85:951-954 (1996)].
In the above cited formulations, nicotinamide apparently operates as a hydrotropic agent to increase the solubility of another solute when nicotinamide is added at a high concentration. This hydrotropic phenomenon is in direct opposition to normal solution behavior where addition of a second solute to a solution of a sparingly soluble substance will cause the less soluble substance to precipitate.
A combination of insulin and nicotinamide, optionally containing a preservative, was previously described by Jorgensen in U.S. Pat. No. 5,382,574. The formulation was reported to promote faster absorption of insulin from an injection site. Jorgensen does not discuss any effect of nicotinamide on formulation stability. Moreover, it is likely that the effect of nicotinamide was not observed or appreciated because the specification specifically recommends that known stabilizing agents such as phospholipids be added to stabilize the formulations. Also, it fails to mention any effect on insulin stability produced by nicotinamide alone.
The molecular interactions in peptide and protein formulations are complex because a variety of factors such as choice of preservative, buffer, ionic strength, pH, temperature, and other excipients must be balanced to produce a relatively stable formulation suitable for manufacturing, shipping, and storage that meets regulatory requirement for such products. The role that each factor contributes to aggregation is uncertain in view of the complexity of the given peptide or protein molecule as well as the propensity for that peptide or protein to aggregate and precipitate in formulations containing preservatives. In view of this complexity and tendency to aggregate, the effect of nicotinamide on the stability of peptides and protein formulations containing a hydrophobic preservative could not have been predicted from the art describing nicotinamide""s effect as a hydrotropic agent for relatively small molecules, nor from its apparent ability to facilitate absorption of insulin from a subcutaneous injection.
Thus, the present invention provides conditions that increase the physical stability of medically useful peptides and proteins in the presence of hydrophobic preservatives and makes possible commercially-viable, multi-use soluble pharmaceutical products to treat a variety of human diseases.
This invention provides a stable soluble formulation comprising a medically useful peptide or protein, a hydrophobic preservative, and nicotinamide.
The invention further provides a process for preparing said formulation which comprises combining a peptide or protein, a hydrophobic preservative, and nicotinamide to produce said formulation.